10-53822433-GAGGAGCAGGAGC-GAGGAGCAGGAGCAGGAGC
Variant summary
Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2BP3
The NM_033056.4(PCDH15):c.5287_5292dupGCTCCT(p.Pro1764_Leu1765insAlaPro) variant causes a conservative inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000016 in 1,437,802 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. P1764P) has been classified as Likely benign.
Frequency
Genomes: not found (cov: 32)
Exomes 𝑓: 0.000016 ( 0 hom. )
Consequence
PCDH15
NM_033056.4 conservative_inframe_insertion
NM_033056.4 conservative_inframe_insertion
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: -0.0150
Publications
2 publications found
Genes affected
PCDH15 (HGNC:14674): (protocadherin related 15) This gene is a member of the cadherin superfamily. Family members encode integral membrane proteins that mediate calcium-dependent cell-cell adhesion. It plays an essential role in maintenance of normal retinal and cochlear function. Mutations in this gene result in hearing loss and Usher Syndrome Type IF (USH1F). Extensive alternative splicing resulting in multiple isoforms has been observed in the mouse ortholog. Similar alternatively spliced transcripts are inferred to occur in human, and additional variants are likely to occur. [provided by RefSeq, Dec 2008]
PCDH15 Gene-Disease associations (from GenCC):
- autosomal recessive nonsyndromic hearing loss 23Inheritance: AR Classification: DEFINITIVE, STRONG, LIMITED Submitted by: Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae), PanelApp Australia
- Usher syndrome type 1Inheritance: AR Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
- Usher syndrome type 1FInheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae), PanelApp Australia
- hearing loss, autosomal recessiveInheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
- nonsyndromic genetic hearing lossInheritance: AR Classification: LIMITED Submitted by: ClinGen
Genome browser will be placed here
ACMG classification
Classification was made for transcript
Our verdict: Uncertain_significance. The variant received 1 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
BP3
Nonframeshift variant in repetitive region in NM_033056.4
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| PCDH15 | NM_033056.4 | c.5287_5292dupGCTCCT | p.Pro1764_Leu1765insAlaPro | conservative_inframe_insertion | Exon 33 of 33 | ENST00000320301.11 | NP_149045.3 | |
| PCDH15 | NM_001384140.1 | c.4368-2209_4368-2204dupGCTCCT | intron_variant | Intron 32 of 37 | ENST00000644397.2 | NP_001371069.1 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| PCDH15 | ENST00000320301.11 | c.5287_5292dupGCTCCT | p.Pro1764_Leu1765insAlaPro | conservative_inframe_insertion | Exon 33 of 33 | 1 | NM_033056.4 | ENSP00000322604.6 | ||
| PCDH15 | ENST00000644397.2 | c.4368-2209_4368-2204dupGCTCCT | intron_variant | Intron 32 of 37 | NM_001384140.1 | ENSP00000495195.1 |
Frequencies
GnomAD3 genomes
GnomAD3 genomes
Cov.:
32
GnomAD2 exomes AF: 0.00000956 AC: 2AN: 209224 AF XY: 0.00 show subpopulations
GnomAD2 exomes
AF:
AC:
2
AN:
209224
AF XY:
Gnomad AFR exome
AF:
Gnomad AMR exome
AF:
Gnomad ASJ exome
AF:
Gnomad EAS exome
AF:
Gnomad FIN exome
AF:
Gnomad NFE exome
AF:
Gnomad OTH exome
AF:
GnomAD4 exome AF: 0.0000160 AC: 23AN: 1437802Hom.: 0 Cov.: 32 AF XY: 0.00000841 AC XY: 6AN XY: 713558 show subpopulations
GnomAD4 exome
AF:
AC:
23
AN:
1437802
Hom.:
Cov.:
32
AF XY:
AC XY:
6
AN XY:
713558
show subpopulations
African (AFR)
AF:
AC:
1
AN:
32130
American (AMR)
AF:
AC:
3
AN:
41668
Ashkenazi Jewish (ASJ)
AF:
AC:
0
AN:
25856
East Asian (EAS)
AF:
AC:
0
AN:
37700
South Asian (SAS)
AF:
AC:
2
AN:
83980
European-Finnish (FIN)
AF:
AC:
0
AN:
51702
Middle Eastern (MID)
AF:
AC:
0
AN:
5670
European-Non Finnish (NFE)
AF:
AC:
17
AN:
1099566
Other (OTH)
AF:
AC:
0
AN:
59530
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.477
Heterozygous variant carriers
0
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0.60
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0.95
Allele balance
Age Distribution
Exome Het
Variant carriers
0
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4
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10
<30
30-35
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>80
Age
GnomAD4 genome
GnomAD4 genome
Cov.:
32
Alfa
AF:
Hom.:
ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
not provided Uncertain:1
Jan 29, 2024
GeneDx
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing
In-frame deletion of 2 amino acids; Not observed at significant frequency in large population cohorts (gnomAD); Has not been previously published as pathogenic or benign to our knowledge -
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
PhyloP100
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at
Publications
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